Heavy alcohol consumption during pregnancy is the leading preventable cause of craniofacial and central nervous system birth defects. These defects include hypodevelopment of the mid-face, microcephaly, and loss of brain tissue mass. Fetal alcohol exposure is especially linked to a significant risk for mental retardation, attention deficits, hyperactivity and other mental health disorders. Alcohol induces a loss of neural tissue by inhibiting neurogenesis while promoting neuronal death. However, the underlying mechanisms are not well understood. We know little about the neurotrophic mechanisms that are targeted by alcohol. We also know little about the gene transcription gestalt that is associated with the deleterious actions of alcohol on the brain. Therefore, our central hypothesis is that is that alcohol suppresses survival and neurogenesis signals, and related patterns of gene expression in the developing cerebral cortex. We will test our hypothesis in cerebral cortical models of neural development. We propose three specific aims: (#1): To identify the extent to which alcohol alters the balance between developmental cell-suicide and survival mechanisms. Our working hypotheses are that alcohol will increase activation of Fas/Apo [apoptosis]-1 suicide receptor and repress compensatory Akt-related survival signals. Furthermore, inhibition of Fas/Apo-1 will prevent alcohol-induced apoptosis. We will test these hypotheses in embryonic mouse cerebral cortical cultures exposed to alcohol. (#2): To identify neural p53-associated genetic differentiation patterns that are regulated by alcohol. p53 is a key intracellular initiator of differentiation. Based on our studies, our working hypothesis is that alcohol alters p53 activation to prevent differentiation-related patterns of gene expression in the cortex. We will use western immunoblot analyses to examine p53 activation, and cDNA microarray analyses to specifically identify p53-associated genes that are regulated by alcohol. (#3) To identify neurogenesis-related genes that are regulated by alcohol in the cerebral cortex. We have identified neurogenesis-related genes in an embryonic cerebral cortical model, using differential hybridization strategies. Based on our data, our working hypothesis is that alcohol will suppress expression of proliferation-associated genes in embryonic cortex. We will use cDNA microarrays to identify relationships between alcohol exposure and induction of genes related to neurogenesis. At the conclusion of the proposed research, we expect to have identified some of the trophic support mechanisms underlying alcohol neurotoxicity. We also expect to identify unique neurogenesis and differentiation gene patterns that are regulated by alcohol during development. These outcomes will be significant because they are expected to provide the foundations for an analysis of neurobiological processes targeted by a leading environmental teratogen.